Quinoline therapeutic agents

ABSTRACT

A series of novel 2-substituted 4-amino-6,7-dimethoxyquinoline derivatives have been prepared, including their pharmaceutically acceptable acid addition salts. These particular compounds are useful in therapy as highly potent antihypertensive agents. Preferred member compounds include 4-amino-2-[4-(2-furoyl)piperazine-1-yl]-6,7-dimethoxyquinoline, 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinoline and 4-amino-6,7-dimethoxy-2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline, respectively. Methods for preparing these compounds from known starting materials are provided.

BACKGROUND OF THE INVENTION

This invention relates to therapeutic agents which are novel derivativesof 4-amino-6,7-dimethoxyquinoline. Such compounds are useful asregulators of the cardiovascular system and, in particular, in thetreatment of hypertension.

SUMMARY OF THE INVENTION

The novel compounds according to the invention are those having theformula: ##STR1## and their pharmaceutically acceptable acid additionsalts, wherein R is --N(C₁ -C₄ alkyl)₂, piperidino,6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl or a group of the formula##STR2## where Y is H, C₁ -C₆ alkyl, aryl, C₁ -C₄ alkyl substituted byaryl, or a nitrogen-containing aromatic heterocyclic group attached tothe adjacent nitrogen atom of the piperazinyl group by a carbon atom, orY is selected from

(a) --COR¹ where R¹ is C₁ -C₆ alkyl, C₁ -C₄ alkyl substituted by aryl,C₃ -C₆ cycloalkyl, (C₃ -C₆ cycloalkyl)methyl, aryl, styryl or aheterocyclic group;

(b) --CONHR² where R² is C₁ -C₆ alkyl, aryl, C₁ -C₄ alkyl substituted byaryl, (C₂ -C₄ alkenyl)methyl, C₃ -C₆ cycloalkyl or (C₃ -C₆cycloalkyl)methyl; and

(c) --COOR³ where R³ is C₁ -C₆ alkyl, C₁ -C₄ alkyl substituted by aryl,C₂ -C₄ alkyl substituted other than on an α-carbon atom by hydroxy, C₃-C₆ cycloalkyl, (C₃ -C₆ cycloalkyl)methyl, (C₂ -C₄ alkenyl)methyl, oraryl.

The preferred aryl groups are phenyl and naphthyl, and said phenyl groupcan be substituted by, for example, 1 or 2 substituents each selectedfrom halo, CF₃, C₁ -C₄ alkyl and C₁ -C₄ alkoxy, or by a singlemethylenedioxy group.

"Halo" means F, Cl, Br or I.

Alkyl, alkoxy and alkenyl groups can be straight or, when appropriate,branched chain. Preferred alkyl groups have 1 to 4 carbon atoms.

Pharmaceutically acceptable acid addition salts of the compounds of theinvention are those formed from acids which form non-toxic acid additionsalts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acidphosphate, acetate, maleate, fumarate, succinate, lactate, tartrate,citrate, gluconate and p-toluenesulphonate salts.

Examples of R¹ include ##STR3## phenyl, p-fluorophenyl, methyl,cyclopropylmethyl, cyclopentyl, styryl, 2-naphthyl and 2-quinolyl.

Examples of R² include phenyl, cyclopropylmethyl, benzyl, n-propyl andallyl.

Examples of R³ include ethyl, --CH₂ CH(CH₃)₂, --CH₂ C(CH₃)₂ (OH),cyclopropylmethyl, p-fluorophenyl, benzyl and --CH₂.C(CH₃)═CH₂.

When Y is said nitrogen-containing aromatic heterocyclic group, thisincludes, for example, the following: ##STR4##

Detailed Description of the Invention

The compounds of the formula (I), can be prepared as follows:

(1) An N-(1R-substituted-ethylidene)-2-cyano-4,5-dimethoxyaniline (II)may be cyclised to form the correspondingly substituted4-amino-6,7-dimethoxyquinoline (I): ##STR5##

The cyclisation can be carried out using a Lewis acid, e.g. zincchloride, or a base, e.g. lithium diisopropylamide (LDA). Zinc chlorideis preferred when R is said tetrahydroisoquinolyl group or anN-aralkyl-piperazino group. The reaction with zinc chloride is typicallycarried out by heating the reactants, preferably at reflux, in asuitable organic solvent, e.g. dimethylacetamide, for up to about 4hours. The reaction with LDA is typically carried out at low temperature(e.g. -70° C.) in a suitable organic solvent, e.g. tetrahydrofuran,following which the reaction mixture is allowed to warm to roomtemperature. In some cases using LDA, heating may be necessary tocomplete the reaction. The product can then be isolated and purifiedconventionally.

The compounds (II) are obtainable conventionally as is illustrated inthe following Preparations. Typical methods are outlined as follows:

(a) For compounds where R is as defined above in this method except forunsubstituted piperazinyl (Y=H): ##STR6## (b) For compounds in which Ris unsubstituted piperazinyl: ##STR7##

(2) The Compound in which R is ##STR8## can also be prepared bydebenzylation of the corresponding 4-benzylpiperazin-1-yl compound,itself preparable via route (1) above. This can be carried outconventionally using, e.g., H₂ over a Pd/C catalyst.

(3) Compounds in which Y is --COR¹ can be prepared as follows: ##STR9##Q is a facile leaving group, preferably Cl.

The reaction can be carried out conventionally. When Q is Cl, thepresence of a tertiary amine acid acceptor such as triethylamine isdesirable. Generally, heating is unnecessary. Typically the reactantsare stirred together in a suitable organic solvent, e.g. chloroform, at5°-10° C. for 1-2 hours. The reaction mixture can then be allowed toattain room temperature and the product isolated conventionally.

(4) Compounds in which Y is --CONHR² can be prepared as follows:##STR10##

When an isocyanate R².NCO is used, the reaction can again be carried outconventionally, e.g. by stirring the reactants together for a few hours(e.g. 3-6 hours) in a suitable organic solvent, e.g. chloroform. Heatingis again generally unnecessary; the product can be isolated routinely.

When a carbamoyl chloride R².NHCOCl is used, this may be generated insitu by the action of phosgene on the amine R².NH₂ as its hydrochloridesalt in the presence of an acid acceptor such as triethylamine in a dry,cooled organic solvent, such as chloroform at -40°. After allowing thisto warm to ambient temperature and removing excess phosgene, a solutionof the piperazino-quinoline in the same solvent is added slowly withcooling, the mixture stirred until reaction is complete and the productisolated routinely.

(5) Compounds in which Y is --COOR³ can be prepared as follows:##STR11## where Q is a facile leaving group, preferably Cl. Typicallythe reaction is carried out by stirring the reactants together for a fewhours in a suitable organic solvent such as chloroform, preferably, whenQ is Cl, in the presence of an acid acceptor such as triethylamine.Heating is not generally necessary, and the product can be isolated in aroutine manner.

(6) Compounds in which Y is said nitrogen-containing aromaticheterocyclic group can be prepared as follows: ##STR12## where Q is afacile leaving group, preferably Cl. The reaction is typically carriedout by heating the reactants, preferably under reflux, in a suitableorganic solvent, e.g. n-butanol, for up to about 24 hours, after whichthe product can be isolated conventionally.

Certain compounds of the invention can be converted to other compoundsof the invention by conventional means, e.g. a chlorine substituent onan aromatic heterocyclic group Y can be replaced by a phenoxy group oran amino group by reaction with phenol or an amine, respectively, underconditions well known in the art, and an alkenyl-methyl group R³ can beconverted to a hydroxyalkyl-methyl group by treatment with concentratedsulphuric acid, as is also well known in the art.

The pharmaceutically acceptable acid addition salts of the comounds ofthe formula (I) can be prepared by conventional procedurs, e.g. byreacting the free base with the appropriate acid in an inert organicsolvent, and collecting the resulting precipitate of the salt byfiltration or by evaporation of the reaction mixture. If necessary, theproduct may then be recrystallised to purify it.

When the compounds of the invention contain an asymmetric centre, theinvention includes both the resolved and unresolved forms. Resolution ofoptically active isomers can be carried out according to conventionalprior art methods.

The antihypertensive activity of the compounds of the formula (I) isshown by their ability to lower the blood pressure of consciousspontaneously hypertensive rats and conscious renally hypertensive dogs,when administered orally at doses of up to 5 mg/kg.

The compounds of the formula (I) and their salts can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theycan be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules either alone or inadmixture with excipients, or in the form of elixirs or suspensionscontaining flavouring or colouring agents. They can be injectedparenterally, for example, intramuscularly, intravenously orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other solutes, forexample, enough salt or glucose to make the solution isotonic.

Thus the invention also provides a pharmaceutical composition comprisinga compound of the formula (I) or pharmaceutically acceptable acidaddition salt thereof together with a pharmaceutically acceptablediluent or carrier.

It also provides a compound of the formula (I), or a pharmaceuticallyacceptable acid addition salt thereof, for use in treating hypertensionin a human being.

The compounds of the formula (I) and their salts can be administered tohumans for the treatment of hypertension by either the oral orparenteral routes, and will be administered orally at dosage levelswithin the range 1 to 50 mg/day for an average adult patient (70 kg),given in a single dose or up to 3 divided doses. Intravenous dosagelevels will be 1/5th to 1/10th of the daily oral dose. Thus for anaverage adult patient, individual oral doses in tablet or capsule formwill be approximately in the range from 1 to 25 mg of the activecompound. It should however be stated that variations will necessarilyoccur depending on the weight and condition of the subject being treatedand the particular route of administration chosen as will be known tothose skilled in the art.

The invention yet further provides a method of treating a human beinghaving hypertension, which comprises administering to the human anantihypertensive amount of a compound of the formula (I) orpharmaceutically acceptable acid addition salt thereof or pharmaceuticalcomposition as defined above.

The following Examples illustrate the invention. All temperatures are in°C.:

EXAMPLE 1 ##STR13##

A solution of 1,4-benzodioxan-2-carbonyl chloride (0.75 g) in chloroform(10 ml) was added dropwise to a stirred solution of4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (1.0 g) in chloroform(50 ml) with triethylamine (1.06 g) at 5°-10°. The reaction was stirredat 5°-10° for one hour, then allowed to attain room temperature andstirred overnight. The mixture was then evaporated in vacuo and theresidue partitioned between chloroform (50 ml) and sodium carbonatesolution (10%, 50 ml). The chloroform layer was separated, the aqueousphase extracted with chloroform (2×50 ml), the extracts combined, washedwith brine, dried (Na₂ SO₄) and evaporated in vacuo. The residue wasthen taken up in chloroform and chromatographed on silica (Merck 9385,60 g) eluting with chloroform/methanol (100:0→97:3). A solution of thepurified product in chloroform was treated with ethereal hydrogenchloride, evaporated in vacuo and the residue recrystallised fromisopropanol to give 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinolinehydrochloride hydrate (0.28 g), m.p. 201°.

Analysis %: Found: C, 56.7; H, 5.4; N, 11.0. Calculated for C₂₄ H₂₆ N₄O₅.HCl.H₂ O: C, 57.1; H, 5.8; N, 11.1.

EXAMPLES 2 TO 11

The following compounds were prepared similarly to Example 1, startingfrom the same quinoline and the appropriate acid chloride as indicated.After chromatography, the product was crystallised from the solventshown in each case.

    __________________________________________________________________________     ##STR14##                                                                                                         Analysis %                               Example            Form Isolated                                                                         Prepared from, and                                                                      (Theoretical in brackets)                No.  Y             and m.p. (°C.)                                                                 recrystallised from                                                                      C    H  N                               __________________________________________________________________________          ##STR15##    Hydrochloride 1/4 hydrate, 270°                                                2-furoyl chloride, MeOH/Et.sub.2 O                                                      56.7 (56.7                                                                         5.5 5.6                                                                          13.5 13.2)                       3                                                                                   ##STR16##    Hydrochloride 1/2 hydrate 301°                                                 benzoyl chloride, MeOH                                                                  60.2 (60.3                                                                         5.7 6.0                                                                          12.7 12.8)                       4                                                                                   ##STR17##    HCl.1.5H.sub.2 O, 215-220° C.                                                  Acetyl chloride, (i) EtOH (ii)                                                          52.1 (51.8                                                                         6.5 6.7                                                                          14.1 14.2)                       5                                                                                   ##STR18##    HCl, 292° C.                                                                   Cyclopentane carbonylchloride, IPA/MeOH                                                 59.8 (59.9                                                                         7.0 6.9                                                                          13.5 13.3)                       6                                                                                   ##STR19##    HCl.0.5H.sub.2 O, 240-241° C.                                                  cinnamoyl chloride, EtOH                                                                61.8 (62.1                                                                         6.0 6.1                                                                          12.0 12.1)                       7                                                                                   ##STR20##    HCl.0.5H.sub.2 O, >300° C.                                                     2-naphthoyl chloride, MeOH/Et.sub.2 O                                                   64.3 (64.0                                                                         5.8 5.8                                                                          11.6 11.5)                       8                                                                                   ##STR21##    HCl.1.5H.sub.2 O, 238-239° C.                                                  Quinoline-2- carbonyl chloride EtOH/MeOH                                                 59.3 (59.2                                                                        5.4 5.8                                                                          13.9 13.8)                       9                                                                                   ##STR22##    HCl.0.5H.sub.2 O, 300-301° C.                                                  Piperonoyl chloride, MeOH                                                               57.2 (57.3                                                                         5.4 5.4                                                                          11.6 11.6)                       10                                                                                  ##STR23##    HCl. 274° C.                                                                    -p-Fluorobenzoyl chloride, hexane IPA                                                  58.5 (59.1                                                                         5.7 5.4                                                                          12.3 12.5)                       11                                                                                  ##STR24##    HCl.H.sub.2 O, 251-252° C.                                                     chroman-2- carbonylchloride, IPA                                                        59.6 (59.7                                                                         5.9 6.2                                                                          11.2 11.1)                       __________________________________________________________________________

EXAMPLE 12 ##STR25##

Phenylisocyanate (1.1 g) was added to a stirred suspension of4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (0.72 g) in chloroform(25 ml) at room temperature and the reaction mixture was stirred for 4hours. The mixture was evaporated in vacuo, the residue taken up inmethanol-chloroform and treated with ethereal hydrogen chloride. Thecrude product was purified by chromatography on silica gel eluting withmethylene chloride followed by chloroform/methanol and thenrecrystallised from methanol/ether to give4-amino-6,7-dimethoxy-2-[4-(N-phenylcarbamoyl)piperazin-1-yl]quinolinedihydrochloride (0.18 g), m.p. 235°.

Analysis %: Found: C, 55.1: H, 5.7; N, 14.7. Calculated for C₂₂ H₂₅ N₅O₃ 2HCl: C, 55.0; H, 5.7; N, 14.6.

EXAMPLES 13 TO 15

The following compounds were prepared similarly to Example 12, using theappropriate isocyanate R².NCO as indicated, and the product crystallisedfrom the solvent shown in each case. ##STR26## In Example 13chromatography was not necessary, while in Examples 14 and 15 thereaction mixtures were purified as in Example 16, i.e. chromatographedas the free base and (in the case of Example 14) then converted to thehydrochloride.

    __________________________________________________________________________                                    Analysis %                                    Example       Form Isolated                                                                         Prepared from, and                                                                      (Theoretical in brackets)                     No.  R.sup.2  and m.p. (°C.)                                                                 recrystallised from                                                                     C    H N                                      __________________________________________________________________________    13   --CH.sub.2 CH.sub.2 CH.sub.3                                                           HCl.1.5H.sub.2 O                                                                       -n-propyl                                                                              54.0 6.8                                                                             16.7                                                 200° (d)                                                                       isocyanate,                                                                             (54.5                                                                              7.0                                                                             16.7)                                                        MeOH/Et.sub.2 O                                         14   --CH.sub.2 C.sub.6 H.sub.5                                                             HCl,    Benzyl isocyanate,                                                                      59.8 6.1                                                                             14.9                                                 269-270° C.                                                                    IPA       (60.3                                                                              6.2                                                                             15.3)                                  15   --CH.sub.2 CH═CH.sub.2                                                             H.sub.2 O,                                                                            Allyl isocyanate,                                                                       58.3 6.7                                                                             17.8                                                 178-181° C.                                                                    EtOAc/CH.sub.2 Cl.sub.2 /                                                               (58.6                                                                              7.0                                                                             18.0)                                                (d)     hexane                                                  __________________________________________________________________________

EXAMPLE 16 ##STR27##

(Aminomethyl)cyclopropane hydrochloride (0.25 g) and triethylamine (0.61g) in P₂ O₅ -dried chloroform (15 ml) was added dropwise to a stirredsolution of phosgene in toluene (12.5%, 2.6 ml) at -40°. The reactionmixture was allowed to warm to room temperature and stirred for 0.5hours. Excess phosgene was removed in a steam of nitrogen then asolution of 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (0.3 g) inP₂ O₅ -dried chloroform (30 ml) was added dropwise at 10° and thereaction mixture stirred at room temperature for 1.5 hours. Sodiumcarbonate solution (10%, 10 ml) was then added and the chloroform layerseparated. The aqueous phase was extracted with chloroform, the organicphases combined, washed with water, dried (MgSO₄) and evaporated invacuo. The residue was then taken up in methylene chloride andchromatographed on silica (Merck 9385, 85 g) eluting with methylenechloride/methanol (100:0→85:15). A solution of the purified product inmethylene chloride was treated with ethereal hydrogen chloride,evaporated in vacuo and the residue recrystallised from isopropanol togive4-amino-2-[4-(N-cyclopropylmethylcarbamoyl)piperazin-1-yl]-6,7-dimethoxyquinolinehydrochloride hemihydrate (165 mg), m.p. 220°-223° (d).

Analysis %: Found: C, 55.6; H, 6.5; N, 16.4. Calculated for C₂₀ H₂₇ N₅O₃.HCl,0.5H₂ O: C, 55.7; H, 6.8; N, 16.3.

EXAMPLE 17 ##STR28##

4-Amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (1.26 g) and2-chloro-4-dimethylaminopyrimidine (0.76 g) in n-butanol (60 ml) wereheated under reflux for 16 hours. The mixture was then evaporated invacuo, the residue partitioned between chloroform and sodium carbonatesolution (10%) and the aqueous phase extracted with chloroform. Thecombined extracts were washed with water, dried (Na₂ SO₄), evaporated invacuo and the residue chromatographed on silica gel (Merck 9385).Elution with chloroform-methanol (100:0→95.5) followed by treatment ofthe product with ethereal hydrogen chloride and recrystallisation frommethanol gave4-amino-6,7-dimethoxy-2-[4-(4-dimethylaminopyrimidin-2-yl)piperazin-1-yl]quinolinedihydrochloride dihydrate (0.19 g), m.p. 260°-263°.

Analysis %: Found: C, 48.4; H, 5.8; N, 18.9. Calculated for C₂₁ H₂₇ N₇O₂.2HCl.2H₂ O: C, 48.7; H, 6.4; N, 18.9.

EXAMPLES 18 TO 26

The following compounds were prepared similarly to Example 18, using theappropriate halogenated heterocyclic compound YQ as. indicated, and theproduct crystallised from the solvent shown in each case. In Example 20chromatography was not necessary.

    __________________________________________________________________________     ##STR29##                                                                                                        Analysis %                                Example          Form Isolated                                                                          Prepared from, and                                                                      (Theoretical in brackets)                 No.  Y           and m.p. (°C.)                                                                  recrystallised from                                                                      C    H  N                                __________________________________________________________________________    18                                                                                  ##STR30##  HCl.2H.sub.2 O 271°                                                             2-chlorobenz- oxazole, MeOH                                                             55.6 (55.3                                                                         5.5 5.9                                                                          14.2 14.7)                        19                                                                                  ##STR31##  2HCl.CH.sub.3 OH, 282-283° C.                                                   2-chloro-4- methylpyrimidine, MeOH                                                      51.7 (52.0                                                                         6.1 6.2                                                                          17.8 17.3)                        20                                                                                  ##STR32##  HCl.2H.sub.2 O 267-269° C.                                                      2-chloro-4- ethoxypyrimidine EtOH                                                       51.7 (52.2                                                                         5.8 6.5                                                                          17.2 17.4)                        21                                                                                  ##STR33##  2HCl.1.5H.sub.2 O 266-268° C. dec.                                              6-chloro-2,4- dimethoxy- triazine,                                                      45.2 (45.5                                                                         5.1 5.7                                                                          18.5 18.6)                        22                                                                                  ##STR34##  2HCl 1.5H.sub.2 O, 247-248° C.                                                  6-chloro-2,4-bis (ethylamino) triazine,                                                 47.8 (47.7                                                                         6.2 6.6                                                                          22.5 22.8)                        23                                                                                  ##STR35##  H.sub.2 O 262-266° C. dec.                                                      3,6-dichloro- pyridazine, not                                                           54.3 (54.5                                                                         5.2 5.5                                                                          19.9 20.1)                        24                                                                                  ##STR36##  2HCl, 244-247° C. dec.                                                          2-Bromothiazole, MeOH                                                                   49.2 (48.7                                                                         5.2 5.2                                                                          15.8 15.8)                        25                                                                                  ##STR37##  2HCl 3H.sub.2 O, 245-252° C. dec.                                               2-chloro-1- methylbenz- imidazole,                                                      50.3 (50.6                                                                         5.5 6.3                                                                          14.8 15.4)                        26                                                                                  ##STR38##  0.5H.sub.2 O, 245-247° C.                                                       2,4-dichloro- pyrimidine, (1) not                                                       55.2 (55.7                                                                         5.5 5.4                                                                          20.2 20.5)                        __________________________________________________________________________     (1) carried out in ethanol at room temperature in the presence of             triethylamine.                                                           

EXAMPLE 27 ##STR39##

4-Amino-2-[4-(2-chloropyrimidin-4-yl)piperazin-1-yl]-6,7-dimethoxyquinolinehemihydrate (0.32 g), phenol (0.15 g), anhydrous potassium carbonate(0.22 g) and potassium iodide (catalytic trace) in 4-methyl-2-pentanone(125 ml) were stirred under reflux for 18 hours. Further portions ofphenol, anhydrous potassium carbonate and potassium iodide were thenadded thrice at 8 hour intervals, followed by a final 18 hoursrefluxing. After cooling, methylene chloride (50 ml) and methanol (20ml) were added and the reaction mixture filtered. The filtrate wasevaporated in vacuo and the residue dissolved in methylene chloride,washed with water, dried (MgSO₄) and evaporated in vacuo. Chromatographyon silica (Merck 9385, 40 g) eluting with methylene chloride/methanol(100:0→88:12) followed by treatment of the product with etherealhydrogen chloride and recrystallisation from isopropanol gave4-amino-6,7-dimethoxy-2-[4-(2-phenoxypyrimidin-4-yl)piperazin-1-yl]quinolinedihydrochloride (0.26 g), m.p. 199°-201° (d).

Analysis %: Found: C, 56.1; H, 5.2; N, 15.7. Calculated for C₂₅ H₂₆ N₆O₃.2HCl: C, 56.5; H, 5.3; N, 15.8.

EXAMPLE 28 ##STR40##

4-Amino-2-[4-(2-chloropyrimidin-4-yl)piperazin-1-yl]-6,7-dimethoxyquinolinehemihydrate (0.2 g) and N-methylcyclopentylamine (0.17 g) in n-butanol(20 ml) were stirred under reflux for 60 hours. The mixture was thenevaporated in vacuo, the residue partitioned between chloroform andsodium carbonate solution (10%) and the aqueous phase extracted withchloroform. The combined extracts were washed with water, dried (MgSO₄),evaporated in vacuo and the residue chromatographed on silica gel (Merck9385, 50 g). Elution with methylene chloride/methanol (100.0→85:15)followed by treatment of the product with ethereal hydrogen chloride andrecrystallisation from isopropanol/ether gave4-amino-6,7-dimethoxy-2-[4-(2-N-methylcyclopentylaminopyrimidin-4-yl)piperazin-1-yl]quinolinedihydrochloride sesquihydrate (0.06 g), m.p. 248°-250°.

Analysis %: Found: C, 53.6; H, 6.5; N, 17.2. Calculated for C₂₅ H₃₃ N₇O₂.2HCl.1.5H₂ O: C, 53.3; H, 6.8; N, 17.4.

EXAMPLE 29 ##STR41##

N-[1-(4-Phenylpiperazin-1-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline(2.5 g) in tetrahydrofuran (35 ml) was added to a stirred solution oflithium diisopropylamide [from n-butyl lithium 1.3M in hexane (6.44 ml)and diisopropylamine (1.44 ml)] in tetrahydrofuran (5 ml) at -70°. Theresulting solution was stirred at -70° for 4 hours then allowed toattain room temperature overnight. The mixture was poured into ice-water(100 ml), extracted with chloform (3×200 ml), the combined extractswashed with water, dried (Na₂ SO₄) and evaporated in vacuo. The residuewas taken up in chloroform/methanol, treated with ethereal hydrogenchloride and recrystallised from methanol to give4-amino-6,7-dimethoxy-2-[4-phenylpiperazin-1-yl]quinolinedihydrochloride hemihydrate (0.82 g) m.p. 288°-290°.

Analysis %: Found: C, 56.9; H, 6.0; N, 12.7. Calculated for C₂₁ H₂₄ N₄O₂ 2HCl.1/2H₂ O: C, 56.5; H, 6.1; N, 12.6.

EXAMPLES 30 TO 32

The following compounds were prepared by the same general route as inExample 27, using the appropriate substituted ethylidene compound offormula (II), except that in Example 31 the reaction was completed byheating on a steam bath. In Examples 30 and 32, the crude product waspurified by column chromatography.

    ______________________________________                                         ##STR42##                                                                                                  Analysis % (Theoret-                            Example            Form isolated                                                                            ical in brackets)                               No.    R           m.p.       C     H    N                                    ______________________________________                                        30                                                                                    ##STR43##  HCl, 272-275°                                                                     .sub. 58.9 (59.3                                                                    6.9 6.9                                                                            13.1 13.0)                           31                                                                                    ##STR44##  HCl.1/2H.sub.2 O 285-288°                                                         .sub. 53.8 (53.3                                                                    6.3 6.5                                                                            14.6 14.4)                           32                                                                                    ##STR45##  2HCl.1/2H.sub.2 O 260°                                                            .sub. 47.8 (47.5                                                                    6.0 6.4                                                                            15.1 14.8)                           ______________________________________                                    

EXAMPLE 33 ##STR46##

N-[1-(4-Benzylpiperazin-1-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline(13.5 g) and zinc chloride (4.86 g) in dimethylacetamide (90 ml) werestirred under reflux for 21/2 hours; further zinc chloride (0.5, 0.2 g)was added after 1/2 and 11/2 hours respectively. The mixture was cooled,treated with ether (700 ml, 2×100 ml) and the supernatant discarded eachtime. The residual tar was then treated with sodium hydroxide solution(2N, 100 ml) and methylene chloride (100 ml) and the mixture was stirredat room temperature for 5 minutes. The organic layer was separated, theaqueous phase extracted with methylene chloride and the total organicextracts washed with water. The dried (Na₂ SO₄) extracts were evaporatedin vacuo and the brown residue (˜13 g) purified by chromatography onsilica gel (Merck 9385, 250 g) eluting with chloroform-methanol(100:0→88:12). A sample of the pure product (6.95 g) was taken up inethanol, treated with ethereal hydrogen chloride and evaporated invacuo. The residue was recrystallised from methanol to give4-amino-6,7-dimethoxy-2(4-benzylpiperazin-1-yl)quinoline dihydrochloridesesquihydrate, m.p. 260°-263°.

Analysis %: Found: C, 54.9; H, 5.9; N, 11.5. Calculated for C₂₂ H₂₆ N₄O₂.2HCl.11/2H₂ O: C, 55.2; H, 6.5; N, 11.7.

EXAMPLE 34

4-Amino-6,7-dimethoxy-2-[6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl]quinoline,m.p. 226°-227° was prepared in the same general manner as the previousExample using the corresponding1-[6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl]ethylidene compoundexcept that the crude reaction residue was recrystallised fromisopropanol.

Analysis %: Found: C, 66.0; H, 6.3; N, 10.9. Calculated for C₂₂ H₂₅ N₃O₄ : C, 66.8; H, 6.4; N, 10.6.

EXAMPLE 35 ##STR47##

A solution of isobutylchloroformate (0.11 g) in chloroform (5 ml) wasadded dropwise to a stirred solution of4-amino-6,7-dimethoxy-2-[piperazin-1-yl]quinoline (0.21 g) in chloroform(15 ml) with triethylamine (0.22 g) at 10°. The solution was thenstirred at room temperature for 1 hour and sodium carbonate solution(10%, 10 ml) added. The organic phase was separated, the aqueoussolution extracted with chloroform (2×15 ml) and the total combinedextracts dried (Na₂ SO₄) and evaporated in vacuo. The residue waspurified by chromatography on silica gel (Merck 9385, 25 g) eluting withmethylene chloride-methanol (100:0→93:7), followed by treatment of theproduct with ethereal hydrogenchloride and recrystallisation fromisopropanol to give4-amino-6,7-dimethoxy-2-[4-(isobutoxycarbonyl)-piperazin-1-yl]quinolinehydrochloride sesquihydrate, m.p. 254°-256° (0.065 g).

Analysis %: Found: C, 52.8; H, 6.9; N, 12.2. Calculated for C₂₀ H₂₈ N₄O₄.HCl.11/2H₂ O: C, 53.2; H, 7.1; N, 12.4.

EXAMPLES 36 TO 39

The following compounds were prepared similarly to Example 35, using theappropriate chloroformate ClCOOR₃ as indicated, the product beingcrystallised from the solvent shown in each case. The compound ofExample 38 was obtained as a bi-product from Example 37, ethylchloroformate having been formed in situ due to traces of ethanol in thechloroform reaction solvent.

    ______________________________________                                         ##STR48##                                                                    Ex-                        Prepared                                                                              Analysis %                                 am-              Form Iso- from and                                                                              (Theoretical                               ple              lated and recrystal-                                                                            in brackets)                               No.  R.sup.3     m.p. (°C.)                                                                       lised from                                                                             C    H   N                                ______________________________________                                        36                                                                                  ##STR49##  HCl H.sub.2 O, 244-245° C. dec.                                                  2-methyl- allyl chloro- formate                                                       54.8 (54.5                                                                         6.2 6.6                                                                           12.7 12.7)                        37   CH.sub.2 CH.sub.3                                                                         HCl       Ethyl   53.5 6.3 13.8                                               0.5 H.sub.2 O,                                                                          chloro- (53.3                                                                              6.5 13.8)                                              278-279° C.                                                                      formate (2),                                                                  IPA                                                38                                                                                  ##STR50##  HCl, 285° C.                                                                      -p-Fluoro- phenyl chloro- formate, MeOH                                              56.9 (57.1                                                                         5.2 5.2                                                                           12.1 12.1)                        39                                                                                  ##STR51##  HCl 1.5 H.sub.2 O, 204-206° C. dec.                                              Benzyl chloro- formate, MeOH                                                          57.2 (56.8                                                                         5.8 6.2                                                                           12.0 11.5)                        ______________________________________                                         (1) Prepared in situ.                                                         (2) Formed in situ.                                                      

EXAMPLE 40

2-Methylallyl4-[4-amino-6,7-dimethoxyquinolin-2-yl]piperazine-1-carboxylate (0.21 g)was added to a stirred solution of concentrated sulphuric acid (2 ml)and H₂ O (2 ml) at 10°-15° and stirring maintained at 10°-15° for 3hours. The reaction mixture was basified with sodium hydroxide solution(5N) whilst maintaining temperature below 15° and then extracted withmethylene chloride. The combined extracts were washed with water, dried(MgSO₄) and evaporated in vacuo. Chromatography on silica (Merck 9385,100 g) eluting with methylene chloride/methanol (100:0→85:15) followedby treatment of the product with ethereal hydrogen chloride andrecrystallisation from isopropanol gave 2-methyl-2-hydroxypropyl4-[4-amino-6,7-dimethoxyquinolin-2-yl]piperazine-1-carboxylatehydrochloride hemihydrate (0.05 g), m.p. 280°.

Analysis %: Found: C, 53.6; H, 6.6; N, 12.7. Calculated for C₂₀ H₂₈ N₄O₅.HCl.0.5H₂ O: C, 53.4; H, 6.7; N, 12.5.

EXAMPLE 41 ##STR52##

4-Amino-6,7-dimethoxy-2-(4-benzylpiperazin-1-yl)quinoline (6.2 g) inethanol (300 ml) with 5% Pd/C catalyst was stirred at 50° under anatmosphere of hydrogen (50 p.s.i.) for 20 hours. The mixture was cooled,chloroform (100 ml) added and the solution filtered through "Solkafloc".The solid was washed with chloroform-methanol (1:1, 4×100 ml) and thecombined filtrates evaporated in vacuo. The residue was partitionedbetween chloroform-sodium carbonate solution (10%), the organic layerremoved, the aqueous phase saturated with salt and further extractedwith chloroform. The combined organic extracts were washed with brine,dried (Na₂ SO₄) and evaporated in vacuo to yield4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (2.42 g). Spectroscopyshowed this product to be the same as that of Example 32.

The following Preparations illustrate the preparation of certainstarting materials.

PREPARATION 1 ##STR53##

Phosphorous oxychloride (1.0 ml) was added to a stirred solution ofdimethylacetamide (2.8 ml) in chloroform (10 ml) at room temperature.The mixture was stirred for 5 minutes, 2-cyano-4,5-dimethoxyaniline(1.78 g) added and the reaction stirred under reflux for 4 hours. Themixture was cooled, poured onto ice and extracted with chloroform andthe organic phase discarded. The aqueous layer was basified (solid NaOH)extracted with chloroform, the combined extracts washed with water,dried (Na₂ SO₄) and evaporated in vacuo. A sample of the brown oilyresidue (2 g) was crystallised from diisopropylether to giveN,N-dimethyl-N'-(2-cyano-4,5-dimethoxyphenyl)acetamidine, m.p. 94°-96°.

Analysis %: Found: C, 63.3; H, 6.9; N, 17.2. Calculated for C₁₃ H₁₇ N₃O₂ : C, 63.1; H, 6.9; N, 17.0.

The following compounds were prepared by the same general method asPreparation 1, starting from the appropriate acetyl derivative of theformula R.COCH₃. In Preparation 2 the crude product was purified bycolumn chromatography.

    __________________________________________________________________________     ##STR54##                                                                                                                  Analysis %                                                                    (Theoretical in brackets)       Preparation No.                                                                        R               Form Isolated m.p.                                                                       Molecular Formula                                                                       C     H    N                    __________________________________________________________________________              ##STR55##      crude                Characterised by                                                              spectroscopy                    3                                                                                       ##STR56##      free base 108-109°                                                                C.sub.21 H.sub.24 N.sub.4 O.sub.2                                                       .sub. 69.2 (69.2                                                                    6.7 6.6                                                                            15.3 15.4)           4                                                                                       ##STR57##      free base 136-138°                                                                C.sub.17 H.sub.19 N.sub.4 O.sub.3                                             F.sub.3   .sub. 52.9 (53.1                                                                    4.9 5.0                                                                             14.7 14.6)          5                                                                                       ##STR58##      free base 143-145°                                                                C.sub.22 H.sub.25 N.sub.3 O.sub.4                                                       .sub. 66.0 (66.8                                                                    6.3 6.4                                                                            10.5 10.6)           __________________________________________________________________________

PREPARATION 6 ##STR59##

A solution ofN-[1-(4-trifluoroacetylpiperazin-1-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline(29.5 g) in methanol (400 ml) and sodium hydroxide (2N, 100 ml) wasstirred at room temperature for 3 hours. The mixture was then evaporatedin vacuo, the residue taken up in chloroform (350 ml) washed with waterand dried (Na₂ SO₄). The solution was evaporated in vacuo and the crudeN-(1-[piperazin-1-yl]ethylidene)-2-cyano-4,5-dimethoxyaniline (23 g),used without further purification.

PREPARATION 7 ##STR60##

2-Cyano-4,5-dimethoxyaniline (20 g), a trace of the correspondinghydrogen chloride salt (200 mg) and triethylorthoacetate (40 ml) werestirred at 150° for 1 hour, with removal of ethanol by distillation. Themixture was then evaporated in vacuo and the crude residue of ethylN-(2-cyano-4,5-dimethoxyphenyl)acetimidate (27.95 g) used directly.

PREPARATION 8 ##STR61##

The crude product (26.9 g) from the previous Preparation,N-benzylpiperazine (21 g) and p-toluenesulphonic acid (100 mg) werestirred together at 150° for 2 hours under a slight pressure reduction.On cooling, the residue was taken up in methylene chloride and extractedwith dilute hydrochloric acid (2N, 2×200 ml). The acid layer wasadjusted to pH4 (5N NaOH), extracted with methylene chloride (2×200 ml)and the combined extracts discarded. The aqueous phase was then basifiedto pH9, extracted with methylene chloride (3×200 ml), the combinedextracts washed with brine, dried (Na₂ SO₄) and evaporated in vacuo. Theresidue was purified by column chromatography (Merck 9385 silica, 400 g)eluting with methylene chloride/methanol (100:0→98:2) and a sample ofthe product (11.68 g) was taken up in ethyl acetate-methanol and treatedwith ethereal hydrogen chloride. The solid was treated with ether anddried to giveN-[1-(4-benzylpiperazin-1-yl)ethylidene]-2-cyano-4,5-dimethoxyanilinedihydrochloride hydrate, m.p. 181°-182°.

Analysis %: Found: C, 56.6; H, 6.7; N, 11.9. Calculated for C₂₂ H₂₆ N₄O₂ 2HCl.H₂ O: C, 56.3; H, 6.4; N, 11.9.

We claim:
 1. A compound of the formula: ##STR62## and thepharmaceutically acceptable acid addition salts thereof, wherein R is agroup of the formula: ##STR63## wherein Y is --COR¹ and R¹ is C₁ -C₆alkyl, aralkyl having up to ten carbon atoms in the nuclear ring with upto four carbon atoms in the alkyl moiety, C₃ -C₆ cycloalkyl, (C₃ -C₆cycloalkyl)methyl, aryl having up to ten carbon atoms in the nuclearring, styryl, quinolyl, furyl, tetrahydrofuryl, 1,4-benzodioxan-2-yl,chroman-2-yl or 5-methylthio-1,3,4-oxadiazol-2-yl, and each aryl groupis naphthyl, phenyl or ring-substituted phenyl having up to twosubstituents each selected from halo, CF₃, C₁ -C₄ alkyl or C₁ -C₄ alkoxyor one substituent which is methylenedioxy.
 2. A compound as claimed inclaim 1 wherein R¹ of --COR¹ is methyl, cyclopentyl, cyclopropylmethyl,2-naphthyl, phenyl, p-fluorophenyl, 3,4-methylenedioxyphenyl, styryl,2-quinolyl, 2-furyl, 1,4-benzodioxan-2-yl or chroman-2-yl.
 3. A compoundas claimed in claim 1 wherein R is 4-(2-furoyl)piperazin-1-yl or4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl. 4.4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinoline. 5.4-Amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinoline.6. A pharmaceutical composition suitable for oral or parenteraladministration comprising a pharmaceutically acceptable carrier and aneffective antihypertensive amount of a compound as claimed in claim 1.7. A method for lowering blood pressure in the treatment of ahypertensive subject, which comprises administering to said subject aneffective blood pressure lowering amount of a compound as claimed inclaim 1.